Histone post-translational modifications control the access of transcription factors to the underlying DNA enabling the regulation of eukaryotic genes that are wrapped in nucleosomes. How this occurs is largely unclear and we have little knowledge of the mechanisms by which histones are modified during replication and how such modifications are altered during transcription to enable nucleosome loss and gene activity. This proposal will address the molecular mechanisms by which acetylation of histones takes place during yeast DNA replication and subsequently, how not only histone acetyltransferases (HATs) but also histone deacetylases (HDACs) such as Hos2 and Hda1 are involved in gene activation. Also, the pathway between nucleosome displacement and replacement is a focus of this proposal since our findings argue that `naked' DNA devoid of nucleosomes is not actually naked and proteins, such as topoisomerase II, that coat `naked'DNA help regulate nucleosome assembly and gene activity. Finally, this proposal addresses the unique functions of a novel acetylation site (histone H3 K56) that regulates yeast histone genes and is most often methylated in human cells. Of special interest is not only the mechanism by which acetylation of this site regulates histone genes but how acetylation and methylation of K56 control the master regulators of pluripotency in human embryonic development. It is already known that defects in histone deacetylase mediated pathways and in topoisomerases can influence the progression of cancers. Our basic studies should allow a better understanding of the cancer state and of the very nature of pluripotency in humans leading to novel therapeutic approaches to disease.